Persistent retrovirus infections constitute a major challenge in contemporary human and veterinary medicine. Among the most perplexing retrovirus infections are those caused by lentiviruses, such as HIV. To address the many unique aspects of lentivirus replication and to make correlations with viral pathogenesis, it is essential that animal systems be developed to serve as models for human lentiviruses, where experimental infections are not possible. This fundamental information on lentivirus molecular biology can serve to develop control procedures based on inhibition of virus gene expression, a strategy that becomes increasingly important as the complexities of lentivirus vaccine development become evident. The research program proposed here is designed to use equine infectious anemia virus to study the lentivirus gene expression and toe correlate these findings with viral persistence and pathogenesis. The specific aims of the proposal are: (i) to examine the nature and role of integrated and extrachromosomal proviral DNA in virus replication and cytopathology (ii) to elucidate the patterns of EIAV gene transcription, which appears to display unique characteristics relative to other lentiviruses, (iii) to examine transactivation of infected cell and to identify viral gene products that mediate transactivation, and (iv) to conduct site directed mutagenesis/deletion studies of infectious viral clones to study the mechanisms of transactivation and pathogenesis. In the first three objectives, a special focus will be to compare cytopathic and noncytopathic infections in selected cell cultures and in monocytes/macrophages isolated from experimentally infected ponies during various stages of disease. In the transactivation studies, we propose to examine the role of transactivation in virus replication in pathogenesis in both cell cultures and experimentally infected animals. This latter aspect is a unique feature made possible by the animal models developed in our laboratories. Thus, the results of these studies should provide fundamental information on the flow of genetic information during a lentivirus infection and establish correlations with persistence and cytopathology.